Opportunities for Improving Techniques for Interspecies Extrapolation in the Risk Assessment Process

Quantitative estimates of human carcinogenic risk from chemical exposure are currently derived primarily from linearized multistage model analyses of the tumor response as observed in chronic laboratory animal bioassays versus administered dose. The numerous ad hoc assumptions that provide a rationale for this generic approach to carcinogenic risk assessment can only be evaluated critically when mechanistic data directly relevant to the low-dose and interspecies extrapolation problems are available. Clear needs exist to develop such ancillary data bases and the means for explicitly incorporating them into the risk estimation process. Target site dosimetry provides one useful organizing concept. Physiological response modeling can account systematically for interspecies variations in the distribution and disposition of chemicals in relation to external measures of exposure. Direct measurements of interactions of chemicals and their metabolites with specific target macromolecules can provide sensitive and biologically meaningful exposure indices. Alternatively, quantitation of toxic effects such as altered cell regulation and differentiation can serve the same purpose. Virus and oncogene activation, DNA damage and repair, and enhanced cell proliferation provide additional biological markers of exposure. They may also comprise critical elements of the carcinogenic process. Identification of the actual mechanisms involved should eventually lead to the development of risk assessment models that adequately reflect the unique biological and toxicological characteristics of different species-chemical combinations.